In developed societies, aging of the population is leading to an increase in the number of patients suffering from dementia. Most of these individuals suffer from Alzheimer's disease (AD). Among the non AD dementias, dementia with Lewy bodies (DLB) is of high prevalence. DLB designates a clinical-pathological syndrome of dementia associated with the cortical and subcortical presence of Lewy bodies in varying degrees, such as diffuse Lewy body disease, senile dementia of the Lewy body type and also Lewy body variant of Alzheimer's disease. Clinical-pathological classification of this dysfunction, which has been named dementia with Lewy bodies (DLB) (I. G. McKeith, D. Galasko, and K. Kosaka, et al., Consensus guidelines for the clinical and pathological diagnosis of Dementia with Lewy bodies (DLB): report on the Consortium on DLB International Workshop Neurology 1996; 47:1113-24.2000; 54:1050-8) also take into account traits common with the characteristics of the AD and of the Parkinson's disease (PD). As a whole, clinical data of the disease may suggest the diagnosis of diffuse Lewy body disease, but there are no definitive diagnostic tests for this disease. Neuropathological examination is at present the only form of diagnosis since it shows pathognomonic alterations by their characteristics, localization and distribution intrinsic of the disease.
Neurological criteria of diagnosis take into account symptoms or nuclear signs. Thus, considered in the evaluation of the dementia with Lewy bodies are attentional, executive and visual-spatial deficits, often most severe, and short-term memory, relatively less severe, than in AD. In the evaluation of fluctuating cognition, a variable temporal course of altered levels of attention and consciousness and the lack of sundown syndrome is encountered. Other key symptoms are recurrent and elaborate visual hallucinations. Typically, these include animated subjects with a variable degree of penetration. In DLB, the spontaneous extrapyramidal signs are rigidity, bradikynesia and motor abnormality; tremor at rest is infrequent. Presence of clinical fluctuations from one day to the next or from one week to the next, especially at the beginning, are aspects that reinforce the diagnosis of DLB. One aspect that might improve the diagnostic sensitivity are criteria to define threshold and scale of the nuclear traits of extrapyramidal motor signs and of visual hallucinations. A further limitation of the current criteria is that characteristics suggestive for diagnosis are not explicitly included in the algorithm used to determine the possible or probable nature of the DLB. To achieve higher precision in diagnosis of DLB, it would be necessary to investigate the utility of the suggestive traits for the differential diagnosis and possible contributions of the sleep alterations (D. I. Kaufer, Dementia and Lewy bodies, Rev. Neurol. 2003 Jul. 16-31; 37(2):127-30, Review).
From a histopathological point of view, the differential signs for a diagnosis of DLB are the presence of Lewy bodies in the cortex and the brain stem, even though in some cases, Lewy neurites, cortical senile plaques, signs of tau pathology or spongiform changes are detected (K. A. Jellinger, Morphological substrates of mental dysfunction in Lewy body disease, an update, J. Neurol. Transm. Suppl. 59 (2000), pp. 185-21). As mentioned above, the characteristics of the lesions (Lewy bodies and neurites), its localization (in neurones neuronal processes) and its distribution (diffuse in the brain stem, amygdala, Meynert's basal nucleus and cerebral cortex) are specific of the disease.
A recent study indicates a clinical incidence of DLB of 26 cases per 100,000 per year, with a maximum rate for the interval of 80-84 years of 68.6 cases per 100,000 per year. This rate is lower than AD, which in a previous study was identified in 93 cases per 100,000 per year but higher than for the fronto-temporal dementia (FTD), is estimated in 14 cases per 100,000 per year. The same study detected a male predominance of the DLB described in the literature, with a percentage of males with DLB versus AD of 63.2% versus 23.1%. In this study, several methodological limitations have to be considered because it is a study with a clinical sample of patients that are not representative of the general population. Also, it has to be taken into account that the insufficient sensitivity of the current clinical criteria may lead to an underestimation of the actual rates. Incidence in the general population may be slightly higher (S. López-Pousa, J. Garre-Olmo, A. Turon-Estrada, E. Gelada-Batile, M. Lozano-Gallego, M. Hernandez-Ferrándiz, V. Morante-Muñoz, J. Peralta-Rodríguez, and M. M. Cruz-Reina, Incidencia clinica de la demencia por cuerpos de Lewy, Rev. Neurol. 2003; 36 (8):715-720).
The etiology of the disease and the molecular mechanisms of its progression are still unknown. However, the main histopathological feature of this disease, accumulation of Lewy bodies, has provided for some of the first clues or indications. Lewy bodies are protein deposits mainly formed by insoluble protein deposits of which the main components are α-synuclein, ubiquitin and ubiquitinated proteins. All of these are members of a subcellular system called UPS system (ubiquitin-proteasome) that is responsible for physiological degradation of defective or overabundant cytoplasmic proteins (A. Herschko and A. Ciechanover (1998), The ubiquitin system, Annu. Rev. Biochem. 67:425-479). Malfunctioning of this system has been described as one of the causes involved in the onset or development of certain neurodegenerative diseases such as AD, PD, Huntington's disease (HD), or Amyotrophic Lateral Sclerosis (ALS) (L. Petrucelli and T. M. Dawson, Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system, Ann. Med. 2004; 36(4):315-20). (P. B. Tran and R. J. Miller, Aggregates in neurodegenerative disease: crowds and power? Trends Neurosci. 1999 May; 22(5):194-7.)
One of the elements of the UPS system (ubiquitin-proteasome) responsible for physiological degradation of defective cytoplasmic proteins is UCH-L1 (ubiquitin carboxy-terminal hydrolase L1), a thiol-protease responsible for the hydrolysis of the peptidic bonds of the protein complexes bound to the carboxyterminal glycine of ubiquitin that lead to regulated destruction of proteins in excess in the cell cytoplasm and releasing ubiquitin that remain available to bind new proteins to be eliminated. The correlation between UCH-L1 and parkinsonism had been described with the detection of a dominant mutation in a German family with a PD history. (E. Leroy, R. Boyer, G. Auburger, B. Leube, G. Ulm, E. Mezey, G. Harta, M. J. Brownstein, S. Jonnalagada, T. Chernova, A. Dehejia, C. Lavedan, T. Gasser, P. J. Steinbach, K. D. Wilkinson, and M. H. Polymeropoulos (1998), The ubiquitin pathway in Parkinson's disease, Nature 395:451-452). Mice defective in UCH-L1 display lower in vivo neuronal ubiquitin levels than wild-type counterparts. In cultured cells, overexpression of UCH-L1 led to an increase in the levels of free ubiquitin (H. Osaka, Y. L. Wang, K. Takada, S. Takizawa, R. Setsuie, H. Li, Y. Sato, K. Nishikawa, Y. J. Sun, M. Sakurai, T. Harada, Y. Hara, I. Kimura, S. Chiba, K. Namikawa, H. Kiyama, M. Noda, S. Aoki, and K. Wada (2003), Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neurons, Hum. Mol. Genet. 12:1945-1958). It has been demonstrated that UCH-L1 colocalizes with other proteins of the UPS system such as ubiquitylated proteins, HSP70, gamma-tubulin and, to a lesser extent, the 20S proteasome and the BiP chaperone (H. C. Ardley, G. B. Scott, S. A. Rose, N. G. Tan, and P. A. Robinson, UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease, J. Neurochem. 2004 July; 90(2):379-91). Recently, it has been described as alterations in the oxidative state of UCH-L1 in sporadic AD and PD (J. Choi, A. I. Levey, S. T. Weintraub, H. D. Rees, M. Gearing, L. S. Chin, and L. Li (2004), Oxidation and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's disease, J. Bio. Chem. 279:13256-13264).
Despite degradation and subcellular protein homeostasis, pathways such as the UPS system and the different proteins that participate in it has been proposed as a key player in the development of diseases such as PD or AD. These share a number of symptoms with the DLB. Causes and mode of progression of this dementia, the second most frequent cause of dementia after AD, are still unknown.
Therapeutic options available to DLB patients are unfortunately very limited, often consisting only in symptomatic treatment to control psychiatric and parkinsonian symptoms. However, anti-parkinsons medication that leads to amelioration in tremor and mobility loss often produces acute and notable worsenings, in some cases fatal, of hallucinatory symptoms and of the psychotic pattern. Also, the prescribed neuroleptic treatment for the psychiatric symptoms produce a notable worsening of the motor pattern. Depending on the pattern showed by the patient, acetyl-cholinesterase inhibitors, dopamine agonists, short- and medium-life benzodiazepines and antidepressants may be of limited help (L. Rampello, S. Cerasa, A. Alvano, V. V. Butta, R. Raffaele, I. Vecchio, T. Cavallaro, E. Cimino, T. Incognito, and F. Nicoletti, Dementia with Lewy bodies: a review, Arch. Gerontol. Geriatr. 2004 July-August; 39(1):1-14.)
Therefore, there is a need for identifying new genes involved in and/or mutations responsible for and/or markers of the dementia with Lewy bodies.
The identification of genes would allow selective molecular diagnosis with regard to other dementias and would allow the diagnosis to be included in common clinical practice.
At the same time, it would produce a significant saving in social and health costs associated to these types of dementias, which are severely incapacitating.
It would also permit adoption of new prognostic and therapeutic orientation criteria in the positive cases since it would permit application to more severe and/or personalized therapies to those cases where the parkinsonian character of the disease is established.
Finally, identification of this/these genes and of possible compounds that might alter its/their expression, delaying or stopping the progression of the disease, would not only permit a selective molecular diagnosis with regard to other dementias, but it would also allow design of selective therapies intended to inactivate those genes.